The peroxisome proliferator-activated receptor (PPAR) is a ligand-dependent transcription factor that belongs to nuclear receptor superfamily such as steroid receptor, retinoid receptor, thyroid receptor, etc. Three isoforms (α type, β (or δ) type and γ type) with different histological distribution have been identified hitherto in human and various animal species (Proc. Natl. Acad. Sci., 1992, 89, 4653). Thereamong, the PPARα is distributed in the liver, kidney, etc. with high catabolic capacity for fatty acids and, in particular high expression is recognized in the liver (Endocrinology, 1995, 137, 354), positively or negatively controlling the expressions of genes relevant to the metabolism and the intracellular transport of fatty acids (e.g. acyl-CoA synthetic enzyme, fatty acid-binding protein and lipoprotein lipase) and apolipoprotein (AI, AII, CIII) genes relevant to the metabolisms of cholesterol and triglyceride. The PPARβ is expressed ubiquitously in the tissues of organisms, including nerve cells. At present, the physiological significance of PPARβ is unclear. The PPARγ is highly expressed in the adipocytes and involved the differentiation of adipocytes (J. Lipid Res., 1996, 37, 907). In this way, each isoform of PPAR plays specific functions in the particular organs and tissues.
Moreover, it is reported that a knock-out mouse of PPARα exhibits hypertriglyceridemia with ageing and becomes obesity mainly by increasing the white adipose tissues (J. Biol. Chem., 1998, 273, 29577), hence the relevance between activation of PPARα and decreasing action of lipids (cholesterol and triglyceride) in blood is suggested strongly.
On the other hand, fibrates and statins are widely used so far as the therapeutic drugs for hyperlipidemia. However, the fibrates have only weak decreasing effect of cholesterol, while the statins have weak decreasing effect of free fatty acids and triqlycerides. Moreover, with respect to the fibrates, various adverse effects such as gastrointestinal injury, anthema, headache, hepatic disorder, renal disorder and biliary calculus are reported. The reason is considered to be due to that the fibrates exhibit extensive pharmacological function, hence the development of a therapeutic drug for hyperlipidemia with specific mechanism is desired.
When considering the present situation of such conventional therapeutic drugs for hyperlipidemia, and the role on the adjusting mechanism of lipid metabolism and the connection to the pathology of hyperlipidemia of transcription factor called PPARα, which has become clear until now, if a compound that binds directly as a ligand of PPARα, in particular, human PPARα and is capable of activating human PPARα could be created, the medicinal use thereof would be expected as a compound that exhibits the decreasing effect of lipids (both of cholesterol and triglyceride) in blood due to very specific mechanism.
For compounds having an affinity to PPARα as ligands of PPARα, eicosanoids in HETE (hydroxyeicosatetraenoic acid) group produced via oxidation with cytochrome P-450, in particular, 8-HETE, 8-HEPE, etc. are reported in addition to LTB4 being a metabolite of arachidonic acid (Proc. Natl. Acad. Sci., 1997, 94, 312). However, these endogenous unsaturated fatty acid derivatives are unstable metabolically and chemically and cannot be offered as medicinal drugs.
On the other hand, as compounds with similar structure to the inventive substituted phenylpropanoic acid derivatives, a group of compounds shown below, etc. are reported.
As α-substituted phenylpropanoic acid derivatives with blood glucose-decreasing action and lipid-decreasing action, in Japanese Unexamined Patent Publication No. Hei 11-158144 (SS Pharmaceutical Co., Ltd.), compounds represented by a general formula (A)

(wherein W denotes a (substituted) lactam ring, A denotes an alkylene group or alkyleneoxy group, X denotes O, S, NH or CH2, Y1 denotes an amino group, hydroxyl group or alkoxy group, R1 denotes H, alkyl group, etc., R2 denotes an alkyl group, phenyl group, etc., and R3 denotes an alkyl group, alkoxy group, etc.) are reported.
However, these compounds have different structure from that of the inventive compounds in the points that carbonyl group or amide group is not contained in A being connecting portion and that lactam ring is contained in W being end substituent, and it is not described that these compounds have the binding activity to human PPARα and the transcription-activating function.
As compounds with blood glucose-lowering action, in International Publication Number WO98/28254 (Nippon Chemiphar Co., Ltd.), compounds represented by a general formula (B)

(wherein A1 denotes an aryl group which may have substituents or heterocycle group, Y2 denotes an alkylene chain with carbon atoms of 1 to 5, X4 denotes bond hand, oxygen atom or sulfur atom, W1 denotes a naphthalene ring which may have substituents, quinoline ring, indole ring, benzisoxazole ring or benzo[b]thiophene ring, R4 denotes a hydrogen atom or alkyl group with carbon atoms of 1 to 8, X5 denotes an oxygen atom or sulfur atom, and R5 denotes an alkyl group with carbon atoms of 1 to 8 which may have substituents, aralkyl group or aryl group), are reported.
However, these compounds have different structure from that of the inventive compounds in the points that carbonyl group or amide group is not contained in Y2 and X4 being connecting portions and that W1 to bind to 3-position of propionic acid is heterocycle, and it is not described that these compounds have the binding activity to human PPARα and the transcription-activating function.
As propanoic acid derivatives with blood glucose-lowering action and lipid-decreasing action, in International Publication Number WO98/07699 (Japan Tobacco Inc.), compounds represented by a general formula (C)

(wherein R denotes a substituent represented by D1 or D2, R1 denotes an aromatic ring, cycloalkyl group or heteroaromatic ring, R5 denotes an alkyl group, R4 denotes a hydrogen atom or alkyl group, R6 denotes a hydrogen atom or it may be connected to R9 to form double bond, R7 denotes a carboxyl group, acyl group, alkoxycarbonyl group which may have substituents, alkyl group, aryloxycarbonyl group, aralkyloxycarbonyl group, carbamoyl group, NHR8 group or OR8 group, R8 denotes an acyl group which may have substituents or alkoxycarbonyl group, R9 denotes a hydrogen atom, alkyl group or alkoxycarbonyl group, and R10 denotes a hydrogen atom, amino group, alkoxy group, alkyl group, aryloxy group or aralkyloxy group), are reported.
However, these compounds also have different structure from that of the inventive compounds in the point that substituents on. benzene ring are of disubstituted form at 1-position and 4-position, and it is not described that these compounds have the binding activity to human PPARα and the transcription-activating function.
As carboxylic acid derivatives with working function on leukotriene receptor, in Japanese Unexamined Patent Publication No. Sho 63-91354 (Yamanouchi Pharmaceutical Co., Ltd.), compounds represented by a general formula (E)

(wherein A denotes a hydrogen atom or phenyl group, m denotes an integer of 3 to 10, n denotes an integer of 1 to 6, X denotes CONH group or NHCO group, and R denotes a carboxy lower alkyl group or carboxy lower alkylcarbamoyl group (however, when A is phenyl group, R is carboxy lower alkylcarbamoyl lower alkyl group)), are reported.
However, since these compounds have no substituent at 2-position of propanoic acid and carbonyl groups exist in all of R group portions, the structure differs from that of the inventive compounds, and it is not described that these compounds have the binding activity to human PPARα and the transcription-activating function.
As carboxylic acid derivatives with antagonism against fibrinogen receptor, in U.S. Pat. No. 5,227,490 (Merck & Co., Inc.), compounds represented by a general formula (F)

(wherein R1 denotes a hydrogen atom, C1-6 alkyl group, aryl C4-10 alkyl group, aryl group, carboxyl group, C1-6 alkoxy group, carboxy C0-6 alkyl group, carboxy C0-6 alkoxy group, hydroxy C1-6 alkyl group, C1-4 alkylsulfonyl C0-6 alkyl group, C0-4 alkylamino C0-6 alkyl group, aryl C0-10 alkylamino C0-6 alkyl group, C2-10 acylamino C0-6 alkyl group, C1-4 carboalkoxy C0-6 alkyl group or halogen atom, R2s denote identically or differently hydrogen atoms, halogen atoms, hydroxyl groups, C1-6 alkoxy groups, aryl C0-4 alkyl groups, aryl C0-6 alkoxy groups or C1-6 alkyl groups which may have substituents, R3 denotes a hydrogen atom, C1-6 alkyl group or aryl C1-10 alkyl group, X denotes an oxygen atom, sulfur atom, SO group, SO2 group, CO group, NR4CO group, CONR4 group, CH2 group, CH═CH group or NR4CS group, Y denotes a C1-10 alkyl group which is unsubstituted or which may have substituents, C4-8 cycloalkyl group, aryl group, C0-3 alkylaryl C0-3 alkyl group, C0-3 alkylaryl C0-3 alkylcarbonyl group, C0-3 alkylaryl C0-3 alkylcarboxyamide group, C0-3 alkylaryloxy C0-3 alkyl group, CONH group, NHCO group or (CH2)m-Q-(CH2)n group (however, Q denotes a C3-8 membered heterocycle containing 1 to 3 kinds of heteroatoms selected from oxygen and sulfur, and m and n denote 0 to 4), and Z denotes a NR4R5 group (however, R4 and R5 denote identically or differently hydrogen atoms, C1-6 alkyl groups, aryl C1-10 alkyl groups in which alkyl group is unsubstituted or may be substituted with C1-4 alkoxy group, carboxy C0-6 alkyl group, hydroxyl group, halogen atom, or 4–9 membered monocyclic or bicyclic ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur) or guanidino group which may have substituents), are reported.
However, from the fact that these compounds are amino acid derivatives inevitably containing amino group which may have substituents, in all of Z group portions, the structure is different from that of the inventive compounds, and it is not described that these compounds have the binding activity to human PPARα and the transcription-activating function.
With respect to patents that report the working function on PPAR α, compounds represented by a general formula (G)

(wherein Ra denotes a 2-benzoxazolyl group or 2-pyridyl group, and Rb denotes a methoxymethyl group or trifluoromethyl group), are reported in International Open Number WO97/25042 (SmithKline Beecham plc.) as compounds with working functions on PPARα and PPARγ. However, the structure of these compounds is different from that of the inventive compounds in the point that substituents on benzene ring are of disubstituted derivatives at 1-position and 4-position, and further it is not described that they have the binding activity to human PPARα and the transcription-activating function.
As compounds with working function on PPARα, in International Publication Number WO97/36579 (Glaxo Welcome Corp.), compounds represented by a general formula (H)

(wherein X denotes a hydrogen atom or fluorine atom), are reported.
However, the structure is different from that of the inventive compounds in the points that these compounds are phenoxyacetic acid derivatives and that the position relationship of substituents on benzene ring is of disubstituted form at 1-position and 4-position. Also, the transcription-activating function of PPARα is never satisfied in strength.
The hyperlipidemia is a risk factor of arterial sclerosis and, from a viewpoint of the prevention of arteriosclerotic diseases, in particular, coronary arteriosclerotic disease, the development of a therapeutic drug for hyperlipidemia with effectiveness and high safety is desired clinically.